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Actimmune

Generic Name: Interferon Gamma
Class: Immunomodulatory Agents
VA Class: IM700
Chemical Name: N2-l-Methionyl-1-139-interferonγ (human lymphocyte protein moiety reduced)
Molecular Formula: C734H1166N204O216S5
CAS Number: 98059-61-1

Introduction

Biologic response modifier; biosynthetic (recombinant DNA origin) form of endogenous human interferon gamma.1 5 6 7

Uses for Actimmune

Chronic Granulomatous Disease

Reduction of the frequency and severity of serious infections in patients with chronic granulomatous disease (designated an orphan drug by FDA for this use).1 5 10 13 20 21 22 24

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Osteopetrosis

Treatment to delay the time to disease progression in patients with severe, malignant osteopetrosis (designated an orphan drug by FDA for this use).1 6 7 13

Idiopathic Pulmonary Fibrosis

Interferon gamma-1b was investigated in patients with idiopathic pulmonary fibrosis (IPF) with mild-to-moderate lung function impairment in the INSPIRE study; the study was terminated early when interim data analysis indicated lack of benefit in patients receiving the drug.26 Interim analysis also indicated that 14.5% of patients receiving interferon gamma 1-b died compared with 12.7% of those receiving placebo.26

Interferon gamma-1b is not approved for use in patients with IPF.26 FDA suggests that health-care professionals should discuss the results of this trial with their patients receiving the drug for IPF and carefully consider whether they should continue to receive treatment with interferon gamma-1b.26

Actimmune Dosage and Administration

General

  • If home use is prescribed, carefully instruct patients and/or their caregivers in appropriate use; provide a puncture-resistant container for proper, safe disposal of used syringes and needles.1

Administration

Sub-Q Administration

Administer by sub-Q injection 3 times weekly (e.g., Monday, Wednesday, Friday).1

Optimum sites for sub-Q injection include right and left deltoid and anterior thigh.1

To minimize risk of flu-like syndrome, administer at bedtime and/or give acetaminophen to prevent or partially alleviate fever and headache.1 5

Vials contain no preservative; discard any residual solution remaining in the vial after administration of the single dose.1

Dosage

Each mg of interferon gamma-1b is approximately equivalent to 20 million international units (equivalent to the amount that formerly was expressed as 30 million units).1

Pediatric Patients

Chronic Granulomatous Disease
Sub-Q

50 mcg/m2 (1 million international units per m2) 3 times weekly for patients with body surface area (BSA) >0.5 m2 and 1.5 mcg/kg 3 times weekly for those with body surface area ≤0.5 m2.1

If a severe adverse reaction (e.g., flu-like symptoms) occurs, reduce dosage by 50% or discontinue drug until adverse reaction abates.1

Osteopetrosis
Sub-Q

50 mcg/m2 (1 million international units per m2) 3 times weekly for patients with body surface area >0.5 m2 and 1.5 mcg/kg 3 times weekly for those with body surface area ≤0.5 m2.1

If a severe adverse reaction (e.g., flu-like symptoms) occurs, reduce dosage by 50% or discontinue drug until adverse reaction abates.1

Adults

Chronic Granulomatous Disease
Sub-Q

50 mcg/m2 (1 million international units per m2) 3 times weekly.1

If a severe adverse reaction (e.g., flu-like symptoms) occurs, reduce dosage by 50% or discontinue drug until adverse reaction abates.1

Osteopetrosis
Sub-Q

50 mcg/m2 (1 million international units per m2) 3 times weekly.1

If a severe adverse reaction (e.g., flu-like symptoms) occurs, reduce dosage by 50% or discontinue drug until adverse reaction abates.1

Prescribing Limits

Pediatric Patients

Chronic Granulomatous Disease
Sub-Q

Safety and efficacy of dosages >50 mcg/m2 3 times weekly not established.1

Osteopetrosis
Sub-Q

Safety and efficacy of dosages >50 mcg/m2 3 times weekly not established.1

Adults

Chronic Granulomatous Disease
Sub-Q

Safety and efficacy of dosages >50 mcg/m2 3 times weekly not established.1

Osteopetrosis
Sub-Q

Safety and efficacy of dosages >50 mcg/m2 3 times weekly not established.1

Cautions for Actimmune

Contraindications

  • Known hypersensitivity to interferon gamma-1b, products derived from Escherichia coli, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Cardiac Effects

Acute and transient flu-like syndrome or constitutional symptoms (e.g., chills, fever)20 24 that are associated with daily dosages ≥250 mcg/m2 (>10 times the weekly recommended dosage) may exacerbate preexisting cardiac conditions.1

Use with caution in patients with preexisting cardiac disease (e.g., arrhythmia, CHF, symptoms of ischemia).1

CNS Effects

Possible seizures, decreased mental status, dizziness, and gait disturbance, particularly at daily dosages >250 mcg/m2 (>10 times the weekly recommended dosage).1

Use with caution in patients with known seizure disorders or compromised CNS function.1

Hematologic Effects

Possibly severe, reversible, dose-limiting neutropenia and thrombocytopenia reported rarely.1

Use with caution in patients with myelosuppression and in those receiving drugs that may be myelosuppressive.1

Monitor blood cell and differential counts and platelet counts prior to initiating interferon gamma-1b and at 3-month intervals during therapy.1

Renal Effects

Proteinuria reported rarely.1

Perform urinalysis and monitor appropriate blood chemistry tests prior to initiating interferon gamma-1b and at 3-month intervals during therapy.1

Hepatic Effects

Possibly substantial (up to 25-fold) elevations of AST and/or ALT reported; children <1 year of age most at risk (see Pediatric Use under Cautions).1 Reversible with dosage reduction or interruption of therapy.1

Perform liver function tests prior to initiating interferon gamma-1b and at monthly (for children <1 year of age) or 3-month intervals during therapy.1 If severe hepatic enzyme elevations occur, modify dosages.1 (See Dosage under Dosage and Administration.)

Sensitivity Reactions

Hypersensitivity Reactions

If acute, serious hypersensitivity reactions occur, discontinue immediately and initiate appropriate therapy.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether interferon gamma-1b is distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Increased risk of elevations of AST and/or ALT in children <1 year of age.1 May occur as early as 7 days after starting treatment.1 (See Hepatic Effects under Cautions.)

Possibly reversible alkaline phosphatase elevation and hypokalemia.1

Common Adverse Effects

Flu-like syndrome (e.g., headache, fever, chills, myalgia, fatigue),1 3 5 8 10 18 erythema or tenderness at injection site,1 injection site hemorrhage,1 nausea,1 vomiting,1 rash.1

Interactions for Actimmune

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comments

Myelosuppressive agents

Possible additive myelosuppressive effects1

Use with caution1

Actimmune Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, >89% of dose is slowly absorbed; peak plasma concentrations attained 7 hours after dose.1

Elimination

Half-life

5.9 hours following a single sub-Q dose.1

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze.1 Unentered vials may be exposed to room temperature for up to 12 hours prior to use; discard vials not returned to refrigerator or used within 12 hours.1

Avoid shaking or excessively or vigorously agitating vials.1

Actions

  • Specific effects of interferon gamma include the enhancement of the oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), activation of natural killer (NK) cells, and the expression of Fc receptors and major histocompatibility antigens.1 2

  • The exact mechanism(s) of action of interferon gamma-1b in patients with chronic granulomatous disease have not been fully elucidated;1 3 4 5 8 9 10 the drug appears to enhance phagocyte function to allow more effective killing of catalase-positive organisms.1 8 Changes in superoxide levels during therapy with interferon gamma-1b do not predict efficacy and should not be used to assess patient response to therapy.1

  • Mechanisms of action in treatment of osteopetrosis not fully elucidated1 12 15 but may involve enhanced superoxide production in leukocytes and osteoclasts.1 Changes in superoxide levels during therapy with interferon gamma-1b do not predict efficacy and should not be used to assess patient response to therapy.1

Advice to Patients

  • Importance of advising patients not to administer the drug until their clinician has thoroughly trained them on proper administration methods (including aseptic technique) and proper disposal of used needles and syringes.1 27

  • Advise patients to notify their clinician if injection site reactions (e.g., persistent lumps, swelling, bruising, signs of infection or inflammation [pus, redness, pain]) occur.27

  • Risk of myelosuppression and adverse hepatic effects.1

  • Importance of taking interferon gamma-1b as prescribed.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Interferon Gamma-1b (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

100 mcg/0.5 mL (2 million international units)

Actimmune

InterMune

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. InterMune, Inc. Actimmune (interferon gamma-1b) prescribing information. Brisbane, CA; 2009 Jan.

2. Gallin JI, Farber JM, Holland SM et al. Interferon-γ in the management of infectious diseases. Ann Intern Med. 1995; 123:216-24. [IDIS 350164] [PubMed 7598304]

3. Todd PA, Goa KL. Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease. Drugs. 1992; 43:111-22. [PubMed 1372855]

4. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med. 2000; 343:1703-14. [PubMed 11106721]

5. International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med. 1991; 324:509-16. [PubMed 1846940]

6. Key LL, Rodriguiz RM, Willi SM et al. Long-term treatment of osteopetrosis with recombinant-human interferon gamma. N Engl J Med. 1995; 332:1594-9. [IDIS 347518] [PubMed 7753137]

7. Key LL, Ries WL, Rodriguiz RM et al. Recombinant human interferon gamma therapy for osteopetrosis. J Pediatr. 1992; 121:119-24. [IDIS 299963] [PubMed 1320672]

8. Ahlin A, Elinder G, Palmblad J. Dose-dependent enhancement of interferon-γ on functional responses of neutrophils from chronic granulomatous disease patients. Blood. 1997; 89:3396-401. [IDIS 385789] [PubMed 9129047]

9. Ahlin A, Larfars G, Elinder G et al. Gamma interferon treatment of patients with chronic granulomatous disease is associated with augmented production of nitric oxide by polymorphonuclear neutrophils. Clin Diag Lab Immunol. 1999; 6:420-4.

10. Weening RS, Leitz GJ, Seger RA. Recombinant human interferon-gamma in patients with chronic granulomatous disease—European follow up study. Eur J Pediatr. 1995; 154:295-8. [PubMed 7607280]

11. Hayden FG. Antiviral drugs (other than antiretrovirals). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practices of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000:460-91.

12. Madyastha PR, Yang S, Ries WL et al. IFN-gamma enhances osteoclast generation in cultures of peripheral blood from osteopetrotic patients and normalizes superoxide production. J Interferon Cytokine Res. 2000; 20:645-52. [PubMed 10926207]

13. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2002 Oct 15. From FDA web site (). Accessed 2003 Apr 14.

14. Lajeunesse D, Busque L, Menard P et al. Demonstration of an osteoblast defect in two cases of human malignant osteopetrosis. Correction of the phenotype after bone marrow transplant. J Clin Invest. 1996; 98:1835-42. [PubMed 8878435]

15. Whyte MP. Chipping away at marble-bone disease. N Engl J Med. 1995; 332:1639-40. [IDIS 347523] [PubMed 7753145]

16. Janeway CA, Travers P, Walport M et al eds. Immunology. 5th ed. New York, NY: Garland Publishing; 2001. From the National Library of Medicine website ().

17. Tramont EC, Hoover DL. Innate (general or nonspecific) host defense mechanisms. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practices of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000:31-8.

18. Bemiller LS, Roberts DH, Starko KM et al. Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease. Blood Cells Mol Dis. 1995; 21:239-247. [PubMed 8673477]

19. Intermune. Brisbane, CA: Personal communication.

20. Errante PR, Frazão JB, Condino-Neto A. The use of interferon-gamma therapy in chronic granulomatous disease. Recent Pat Antiinfect Drug Discov. 2008; 3:225-30. [PubMed 18991804]

21. Jones LBKR, McGrogan P, Flood TJ et al. Special Article: Chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry Clin Exp Immunol. 2008; 152: 211–218.

22. Kobayashi S, Murayama S, Takanashi S et al. Clinical features and prognoses of 23 patients with chronic granulomatous disease followed for 21 years by a single hospital in Japan. . Eur J Pediatr. . 2008;167:1389-94.

23. Martire B, Rondelli R, Soresina A et al. Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study. Clin Immunol. 2008; 126:155-64. [PubMed 18037347]

24. Marciano BE, Wesley R, De Carlo ES et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004; 39:692-9. [PubMed 15356785]

25. Ma HR, Mu SC, Yang YH et al. Therapeutic effect of interferon-gamma for prevention of severe infection in X-linked chronic granulomatous disease. J Formos Med Assoc. 2003; 102:189-92. [PubMed 12783137]

26. Food and Drug Administration. Information for healthcare professionals–interferon gamma–1b (marketed as Actimmune) From FDA web site http: / / www.fda.gov / Drugs / DrugSafety / PostmarketDrugSafetyInformationforPatientsandProviders / / 2007 / march09.htm.

27. InterMune, Inc. Actimmune (interferon gamma-1b) Information for the patient/caregiver.. Brisbane, CA; 2006 Nov.

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